Methods and compositions using norastemizole in combination with leukotriene inhibitors

ABSTRACT

Methods and pharmaceutical compositions employing norastemizole and a leukotriene inhibitor for the treatment or prevention of inflammation or allergic disorders, such as asthma or the symptoms thereof. Also included are methods and compositions employing norastemizole and a decongestant for the treatment or prevention of inflammation or allergic disorders, such as asthma or the symptoms thereof.

This application is a continuation of Ser. No. 09/059,572, filed Apr.14, 1998, now U.S. Pat. No. 6,248,308.

1. FIELD OF THE INVENTION

The invention relates to methods of treating asthma, inflammation, andallergic conditions. In another aspect, this invention relates to theuse of antihistamines and leukotriene inhibitors, and compositionscontaining them.

2. BACKGROUND OF THE INVENTION

Astemizole is an antagonist of the H-1 histamine receptor protein, whichmediates the response antagonized by conventional antihistamines.Astemizole is well absorbed but is extensively metabolized. See Uchiyamaet al., Pharmarcometrics, 40:7793 (1990). Three main metabolites havebeen identified, all of which are reported to have some antihistaminicactivity. See Kamei et al., Arzneimittel-Forschung/Drug Research,41:932-36 (1991).

Weintraub et al., Hosp. Formul., 22:918-27 (1987) describes clinicalefficacy of astemizole in the treatment of both seasonal and perennialallergies. It has also been suggested that astemizole would be usefulfor the treatment of asthma.

Astemizole is sold commercially as a prescription antihistamine(HISMANAL®), however, the use of astemizole is believed to have apotential for serious cardiotoxicity in certain patients. Norastemizole,one of the metabolites of astemizole, is said to have the beneficialeffects of astemizole while having a reduced risk of cardiotoxicity. Thepreparation of norastemizole is described, e.g.; in WO 94/07495,published Apr. 14, 1994.

Leukotrienes augment neutrophil and eosinopil migration, neutrophil andmonocyte aggregation, leukocyte adhesion, increase capillarypermeability, and smooth muscle 35 contraction, all of which contributeto inflammation, edema, mucus secretion, and bronchoconstriction. Forexample, zileuton, sold commercially as ZYFLO®, is a specific inhibitorof 5-lipoxygenase having the chemical name(±)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known toinhibit leukotriene (LTH₄, LTC₄, LTD₄, and LTE₄) formation in vitro.Zileuton is an inhibitor ex vivo of LTB₄ formation in several speciesand inhibits leukotriene-dependent smooth muscle contractions in vitroin guinea pig and human airways. One study of 373 patients indicatedthat 600 mg of zileuton four times daily were required to provideefficacy, while 400 mg failed to do so. In some patients, zileuton wasreported to cause headache, pain, asthenia, dyspepsia, nausea, andmyalgia. [Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 474-76 (1998)].

Zafirlukast, sold commercially as ACCOLATE®, is another type ofleukotriene inhibitor. This leukotriene inhibitor is a leukotrienereceptor antagonist (LTRA) of leukotriene D₄ and E₄, and has thechemical name4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide.Cysteinyl leukotriene production and receptor occupation have beencorrelated with the pathophysiology of asthma. In vitro studiesindicated that zafirlukast antagonized the contractile activity of threeleukotrienes in conducting airway smooth muscle from laboratory animalsand humans; prevented intradermal LTD₄-induced increases in cutaneousvascular permeability; and inhibited inhaled LTD₄-induced influx ofeosinophils into animal lungs. In some patients, zafirlukast has beenreported to cause headache, infection, nausea, diarrhea, pain, asthenia,abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, anddyspepsia. [Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 3148-49 (1998)].

3. SUMMARY OF THE INVENTION

The present invention represents an improvement over the astemizole andnorastemizole, as well as the leukotriene inhibitor, technologypresently available.

This invention relates to novel pharmaceutical compositions containing(a) norastemizole, or a pharmaceutically acceptable salt thereof, and(b) a leukotriene inhibitor, or a pharmaceutically acceptable saltthereof, and optionally (c) a decongestant, and a pharmaceuticallyacceptable carrier or excipient.

The compositions of the invention employing norastemizole and aleukotriene inhibitor, and optionally a decongestant, possess potentantihistaminic activity and are useful in treating, preventing, ormanaging asthma, asthma symptoms, inflammation, allergic rhinitis, andother allergic disorders, as well as dermatitis. The compositionsemploying norastemizole and a leukotriene inhibitor provide an improvedoverall therapy relative to either norastemizole or the leukotrieneinhibitor alone. Additionally, the novel pharmaceutical compositions ofthe invention are useful in treating, preventing, or managing motionsickness, vertigo, diabetic retinopathy, small vessel complications dueto diabetes and such other conditions as may be related to the activityof the norastemizole as an antagonist of the H-1 histamine receptor. Thecompositions of the invention are also useful in combination withnon-steroidal anti-inflammatory agents or other non-narcotic analgesics,and are useful for the treatment of cough, cold, cold-like, and/or flusymptoms and the discomfort, headache, pain, fever, and general malaiseassociated therewith. The aforementioned combinations (e.g.,norastemizole and a leukotriene inhibitor) may optionally include one ormore other active components including a decongestant, coughsuppressant/antitussive, or expectorant.

The compositions of the invention can be used to treat, prevent, ormanage the disorders described herein while reducing or avoiding adverseeffects associated with administration of other non-sedatingantihistamines, such as astemizole.

In one embodiment, this invention provides a method of preventing ortreating asthma or the symptoms of asthma in a human which comprisesadministering to a human a therapeutically effective amount ofnorastemizole, or a pharmaceutically acceptable salt thereof, and atherapeutically effective amount of a leukotriene inhibitor, or apharmaceutically acceptable salt thereof.

The invention also provides a method of treating or preventing asthma orthe symptoms of asthma in a human which comprises administering to ahuman a composition, said composition comprising (i) a therapeuticallyeffective amount of norastemizole or a pharmaceutically acceptable saltthereof; (ii) a leukotriene inhibitor selected from the group consistingof 5-lipoxygenase inhibitors, 5-lipoxygenase activating proteinantagonists, and leukotriene receptor antagonists, or a pharmaceuticallyacceptable salt thereof; (iii) optionally a therapeutically effectiveamount of a decongestant; and a pharmaceutically acceptable carrier orexcipient.

This invention also includes a method of preventing or treating asthmaor the symptoms of asthma in a human which comprises administering to ahuman a therapeutically effective amount of norastemizole, or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of a leukotriene inhibitor, or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a decongestant.

In a second embodiment, the invention also provides for a method ofpreventing or treating allergic rhinitis in a human which comprisesadministering to a human a therapeutically effective amount ofnorastemizole, or a pharmaceutically acceptable salt thereof, and eithera leukotriene inhibitor or a decongestant, or both, such that all threeactive ingredients are used.

In a third embodiment, the invention also provides for a method ofpreventing or treating dermatitis in a human which comprisesadministering to a human a therapeutically effective amount ofnorastemizole, or a pharmaceutically acceptable salt thereof, and eithera leukotriene inhibitor or a decongestant, or both, such that all threeactive ingredients are used.

In a fourth embodiment, the invention also provides for a method ofpreventing or treating inflammation in a human which comprisesadministering to a human a therapeutically effective amount ofnorastemizole, or a pharmaceutically acceptable salt thereof, and aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof.

The invention also provides a method of preventing or treatinginflammation in a human which comprises administering to a human acomposition, said composition comprising (i) a therapeutically effectiveamount of norastemizole or a pharmaceutically acceptable salt thereof;(ii) a leukotriene inhibitor selected from the group consisting of5-lipoxygenase inhibitors, 5-lipoxygenase activating proteinantagonists, and leukotriene receptor antagonists, or a pharmaceuticallyacceptable salt thereof; (iii) optionally a therapeutically effectiveamount of a decongestant; and a pharmaceutically acceptable carrier orexcipient.

This invention also includes a method of preventing or treatinginflammation in a human which comprises administering to a human atherapeutically effective amount of norastemizole, or a pharmaceuticallyacceptable salt thereof, a therapeutically effective amount of aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and a therapeutically effective amount of a decongestant.

In a fifth embodiment, the invention also provides for a method ofpreventing or treating a condition responsive to leukotriene inhibitionin a human which comprises administering to a human a therapeuticallyeffective amount of norastemizole, or a pharmaceutically acceptable saltthereof, and either a leukotriene inhibitor or a decongestant, or both,such that all three active ingredients are used.

The invention encompasses the treatment, prevention and/or management ofasthma or the symptoms of asthma,allergic rhinitis, inflammation, ordermatitis using a metabolite of astemizole, preferably norastemizole,and a leukotriene inhibitor. The invention also encompasses thetreatment, prevention, and/or management of these disorders withnorastemizole and a decongestant. Further, the invention encompasses thetreatment, prevention and/or management of these disorders usingnorastemizole, a leukotriene inhibitor, and a decongestant. Theinvention encompasses the treatment, prevention, and/or management ofthese disorders using a single unit dosage form (solid or liquid;preferably a solid) that contains norastemizole and either a leukotrieneinhibitor or a decongestant, or all three active ingredients. However,it should be recognized that combination therapy by separateadministration of each active ingredient is also contemplated. Themethods and compositions of this invention are believed to reduce oravoid adverse effects associated with administration of non-sedatingantihistamines, such as astemizole. The methods and compositionsdescribed herein are believed to provide superior or improved therapyover prior art methods and compositions involving norastemizole in theabsence of a leukotriene inhibitor, or a leukotriene inhibitor in theabsence of norastemizole. Without being limited by theory, it isbelieved that the combination of norastemizole, a leukotriene inhibitor,and optionally a decongestant, provides superior, improved, andsynergistic effects unachievable by any of these compounds alone.

4. DETAILED DESCRIPTION OF THE INVENTION

The administration of norastemizole, a leukotriene inhibitor, andoptionally a decongestant, in the methods of the present invention maybe made either concurrently or sequentially, i.e., norastemizole, aleukotriene inhibitor, and an optional decongestant may be administeredas a combination, concurrently but separately, or by the sequentialadministration, e.g., of norastemizole, leukotriene inhibitor, anddecongestant, or the sequential administration of a leukotrieneinhibitor, decongestant, and norastemizole. The compositionsadministered in each of these methods may be concurrent, sequential, orin any combination of concurrent and/or sequential.

The major adverse effects to be avoided by the methods and compositionsof the present invention include, but are not limited to,cardiotoxicity, such as cardiac arrythmia.

Astemizole and other non-sedating antihistamines have antihistaminicactivity and provide therapy and a reduction of symptoms for a varietyof conditions and disorders related to allergic rhinitis and otherallergic disorders, diabetes mellitus, and other conditions; however,such drugs, while offering the expectation of efficacy, may causeadverse effects. Utilizing norastemizole in combination with aleukotriene inhibitor, and optionally with a decongestant, results inclearer dose-related definitions of efficacy, diminished adverseeffects, a superior therapy due to synergistic activity, andaccordingly, an improved therapeutic index. It is, therefore, moredesirable to use the compositions and methods of the invention than touse astemizole, or norastemizole, itself or other non-sedatingantihistamines. Norastemizole and its salts can be synthesized, forexample, as described in U.S. Pat. Nos. 4,835,161, 4,556,660, and4,219,559, which are expressly incorporated herein by reference theretofor this purpose.

The term “adverse effects” as used herein includes, but is not limitedto, cardiac arrhythmias, cardiac conduction disturbances, appetitestimulation, weight gain, sedation, gastrointestinal distress, headache,dry mouth, constipation, and diarrhea. The term “cardiac arrhythmias”includes, but is not limited to, ventricular tachyarrhythmias, torsadesde pointes, and ventricular fibrillation.

The phrase “therapeutically effective amount of norastemizole” as usedherein means that amount of norastemizole which provides a therapeuticbenefit in the treatment, management, or prevention of conditions thatare responsive to histamine antagonists, such as urticaria, allergicrhinitis, inflammation, symptomatic dermographism, dermatitis, asthma,allergic asthma, retinopathy or other small vessel disorders associatedwith diabetes mellitus, and the symptoms associated with asthma orallergic rhinitis such as cough, cold, cold-like, wheezing, dyspnea,and/or flu symptoms including, but not limited to, sneezing, rhinorrhea,lacrimation, and dermal irritation.

The phrase “therapeutically effective amount” with respect toleukotriene inhibitor as used herein means that amount of leukotrieneinhibitor that provides a therapeutic benefit in the treatment,prevention, or management of conditions that are responsive toleukotriene inhibitors, such as urticaria, allergic rhinitis,inflammation, symptomatic dermographism, dermatitis, asthma, allergicasthma, retinopathy or other small vessel disorders associated withdiabetes mellitus, and the symptoms associated with asthma or allergicrhinitis such as cough, cold, cold-like, wheezing, dyspnea, and/or flusymptoms including, but not limited to, sneezing, rhinorrhea,lacrimation, and dermal irritation.

The phrase “therapeutically effective amount” with respect todecongestant as used herein means that amount of decongestant alone, orin combination with other drugs, that provides a therapeutic benefit inthe treatment, prevention, or management of any condition that isresponsive to decongestants, such as congestion of the respiratory tractand/or the sinuses, and the symptoms associated with congestion, such ascough, cold, cold-like, wheezing, dyspnea, and/or flu symptomsincluding, but not limited to, sneezing, rhinorrhea, lacrimation, anddermal irritation.

The term “asthma” as used herein is defined as a disorder characterizedby increased responsiveness of the trachea and bronchi to variousstimuli, which results in symptoms that include, but are not limited to,wheezing, cough, shortness of breath, dyspnea, and the like. Asthmaincludes, for example, allergic asthma.

The term “dermatitis” as used herein is that disorder caused byinflammation to the skin including endogenous and contact dermatitissuch as, but not limited to: actinic dermatitis (or photodermatitis),atopic dermatitis, chemical dermatitis, cosmetic dermatitis, dermatitisaestivalis, and seborrheic dermatitis.

The term “inflammation” as used herein is a fundamental pathologicprocess of a dynamic complex of cytologic and chemical reactions thatoccur in the affected blood vessels and adjacent tissues in response toan injury or abnormal stimulation caused by a physical, chemical, orbiologic agent, including: the local reactions and resulting morphologicchanges; the destruction or removal of the injurious material; and theresponses that lead to repair and healing. The typical signs ofinflammation are redness, heat or warmth, swelling, pain, andoccasionally inhibited or lost function. All of the signs may beobserved in certain instances, although any particular sign is notnecessarily always present.

The term “leukotriene inhibitor” as used herein includes any agent orcompound that inhibits, restrains, retards or otherwise interacts withthe action or activity of leukotrienes, such as, but not limited to,5-lipoxygenase (“5-LO”) inhibitors, 5-lipoxygenase activating protein(“FLAP”) antagonists, and leukotriene receptor antagonists (“LTRAs”). Anexemplary LTRA is leukotriene D₄ (“LTD₄”) receptor antagonist.

The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise interacts with the enzymatic action of 5-lipoxygenase, suchas, but not limited to, zileuton, docebenone, piripost, and ICI-D2318.

The term “5-lipoxygenase activating protein antagonist” or “FLAPantagonist” as used herein includes any agent or compound that inhibits,restrains, retards or otherwise interacts with the action or activity of5-lipoxygenase activating protein, such as, but not limited to, MK-591and MK-886.

The term “leukotriene receptor antagonist” or “LTRA” as used hereinincludes any agent or compound that inhibits, restrains, retards orotherwise antagonizes the activity of receptors that are responsive toleukotrienes, including those responsive to leukotriene D₄. ExemplaryLTRAs include, but are not limited to, sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneacetate;1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid or sodium or other salts thereof, pranlukast, zafirlukast(ICI-204219), and montelukast (MK-476), the latter of which is soldcommercially as SINGULAIR®.

The magnitude of a prophylactic or therapeutic dose of norastemizole orleukotriene inhibitor in the acute or chronic management of a disorderor condition will vary with the severity of the condition to be treatedand the route of administration. The dose, and perhaps the dosefrequency, will also vary according to the age, body weight, andresponse of the individual patient. Suitable total daily dose ranges canbe readily determined by those skilled in the art. In general, the totaldaily dose range for norastemizole, for the conditions described herein,is from about 1 mg to about 200 mg administered in single or divideddoses orally, topically, transdermally, or locally by inhalation. Forexample, a preferred oral daily dose range should be from about 10 mg toabout 100 mg. A preferred oral daily dose range of decongestant, such aspseudoephedrine, should be from about 50 mg to about 300 mg, morepreferably, about 150 mg to about 250 mg. In addition, suitable oraldaily dosage ranges of leukotriene inhibitor can be readily determinedby those skilled in the art. For example, see the Physician's DeskReference® 1998 for suitable dosages presently used for knownleukotriene inhibitors. For example, for 5-lipoxygenase inhibitors, theoral daily dose range should be from about 20 mg to 2,500 mg, preferablyfrom about 20 mg to 800 mg. For leukotriene receptor antagonists, theoral daily dose range should be from about 2 mg to 100 mg, preferablyfrom about 5 mg to 20 mg.

It is further recommended that children, patients aged over 65 years,and those with impaired renal or hepatic function initially receive lowdoses, and that they then be titrated based on individual response(s) orblood level(s). It may be necessary to use dosages outside these rangesin some cases as will be apparent to those skilled in the art. Further,it is noted that the clinician or treating physician will know how andwhen to adjust, interrupt, or terminate therapy in conjunction withindividual patient response.

The term “therapeutically effective amount of norastemizole or apharmaceutically acceptable salt thereof” is encompassed by theabove-described dosage amounts. In addition, the terms “said compositioncomprising (i) a therapeutically effective amount of norastemizole or apharmaceutically acceptable salt thereof; and (ii) “a therapeuticallyeffective amount of a decongestant”; “said composition comprising (i) atherapeutically effective amount of norastemizole or a pharmaceuticallyacceptable salt thereof; and (ii) a therapeutically effective amount ofa leukotriene inhibitor”; and “said composition comprising (i) atherapeutically effective amount of norastemizole or a pharmaceuticallyacceptable salt thereof; (ii) a therapeutically effective amount of aleukotriene inhibitor; and (iii) a therapeutically effective amount ofdecongestant” are also encompassed by the above-described dosage amountsand dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of norastemizole according to themethods of the present invention. For example, oral, intraoral, rectal,parenteral, epicutaneous, transdermal, subcutaneous, intramuscular,intranasal, sublingual, buccal, intradural, intraocular,intrarespiratory, or nasal inhalation and like forms of administrationmay be employed. Oral administration is generally preferred. For themethods to treat dermatitis, however, topical administration ispreferred.

The pharmaceutical compositions used in the methods of the presentinvention, which are sterile and stable, include norastemizole, themetabolic derivative of astemizole, and either a leukotriene inhibitor,or a decongestant, or both, as the active ingredients, orpharmaceutically acceptable salts thereof. The compositions may alsocontain a pharmaceutically acceptable carrier or excipient, andoptionally, other therapeutic ingredients. The compositions arepreferably single solid unit doses, e.g., capsules, tablets, or thelike.

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids or bases or organic acids or bases. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, andphosphoric. Appropriate organic acids may be selected, for example, fromaliphatic, aromatic, carboxylic and sulfonic classes of organic acids,examples of which are formic, acetic, propionic, succinic, glycolic,glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic,algenic, and galacturonic. Examples of such inorganic bases includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium, and zinc. Appropriate organic bases may be selected,for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysineand procaine.

The compositions for use in the methods of the present invention caninclude suitable excipients or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, gel caps, syrups, elixirs, gels, powders,magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols, and the like.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compound foruse in the methods of the present invention may also be administered bycontrolled release means and/or delivery devices such as those describedin U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, the disclosures of which are incorporated herein by referencethereto.

Preferred compositions containing norastemizole are lactose free solidoral compositions. Additional preferred suitable compositions containingnorastemizole for use according to the invention include non-hygroscopicand anhydrous norastemizole solid oral compositions.

Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient(s) with the carrier, which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Preferably, the tablet, cachet or capsule containseither of the following dosages: 15 mg, 30 mg, or 45 mg ofnorastemizole, in combination with the leukotriene inhibitor and/ordecongestant.

The invention is further defined by reference to the following exampledescribing in detail the preparation of the composition and thecompositions used in the methods of the present invention, as well astheir utility. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced which arewithin the scope of this invention.

5. EXAMPLES 5.1 Example 1 Preparation of Norastemizole

Norastemizole may be synthesized, for example, by the methods disclosedin U.S. Pat. Nos. 4,219,559 and 4,835,161, which are hereby incorporatedherein by express reference thereto. Norastemizole may also be preparedby the reaction steps disclosed in WO 94/07495, published Apr. 14, 1994.Reaction of an isothiocyanate with phenylenediamine gives acorresponding thiourea. N-Alkylation with p-fluorobenzylbromide gives asecondary amine which, upon cyclization, yields a substitutedbenzimidazole. Treatment of the benzimidazole with base hydrolyzes theurethane moiety to give norastemizole. N-Alkylation of norastemizolewith p-methoxyphenethyl bromide yields astemizole. Astemizole can beconverted to desmethylastemizole by demethylation using, for example, aLewis acid, such as boron trifluoride, boron trichloride, aluminumtrichloride, and the like.

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

The foregoing disclosure includes all the information deemed essentialto enable those skilled in the art to practice the claimed invention.Because the cited patents or publications may provide further usefulinformation these cited materials are incorporated herein in theirentireties by reference thereto.

What is claimed is:
 1. A method of treating or preventing asthma or thesymptoms thereof in a human which comprises administering to a human atherapeutically effective amount of norastemizole, or a pharmaceuticallyacceptable salt thereof, and a therapeutically effective amount of aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof. 2.A method of treating or preventing asthma or the symptoms thereof in ahuman which comprises administering to a human a composition, saidcomposition comprising (i) a therapeutically effective amount ofnorastemizole, or a pharmaceutically acceptable salt thereof; (ii) atherapeutically effective amount of leukotriene inhibitor, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activatingprotein antagonists, leukotriene receptor antagonists, and mixturesthereof; and a pharmaceutically acceptable carrier or excipient.
 3. Themethod of claim 1, wherein the administration of the amountnorastemizole, or a pharmaceutically acceptable salt thereof, and theamount of leukotriene inhibitor, or a pharmaceutically acceptable saltthereof, avoids the concomitant liability of adverse effects associatedwith the administration of non-sedating antihistamines.
 4. The method ofclaim 2, wherein the administration of the amount norastemizole, or apharmaceutically acceptable salt thereof, and the amount of leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof, avoids theconcomitant liability of adverse effects associated with theadministration of non-sedating antihistamines.
 5. The method of claim 1,2, 3, or 4 wherein the administering further comprises a therapeuticallyeffective amount of a decongestant, or a pharmaceutically acceptablesalt thereof.
 6. The method of claim 1 wherein said human has asthma. 7.The method of claim 1, wherein the leukotriene inhibitor is selectedfrom the group consisting of leukotriene D₄, zileuton, docebenone,piripost, ICI-D2318, MK-591, MK-886, sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropane-acetate;1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid, pranlukast, zafirlukast, and montelukast.
 8. The method of claim1, wherein the therapeutically effective amount of norastemizole orpharmaceutically acceptable salt thereof is administered orally,topically, transdermally, or by inhalation.
 9. The method of claim 1,wherein the therapeutically effective amount of the leukotrieneinhibitor or pharmaceutically acceptable salt thereof is administeredorally, topically, transdermally, or by inhalation.
 10. The method ofclaim 2, wherein the leukotriene inhibitor is selected from the groupconsisting of leukotriene D₄, zileuton, docebenone, piripost, ICI-D2318,MK-591, MK-886, sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)-cyclopropane-acetate;1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid, pranlukast, zafirlukast, and montelukast.
 11. The method of claim2, wherein the therapeutically effective amount of norastemizole, orpharmaceutically acceptable salt thereof, is administered orally,topically, transdermally, or by inhalation.
 12. The method of claim 2,wherein the therapeutically effective amount of the leukotrieneinhibitor, or pharmaceutically acceptable salt thereof, is administeredorally, topically, transdermally, or by inhalation.